Pyrrolo[2,3-d]pyrimidine cytokine inhibitors

Abstract

The present invention relates to 2,6,7-substituted pyrrolo[2,3-d]pyrimidines which inhibit the extracellular release of inflammatory cytokines, said cytokines responsible for one or more human or higher mammalian disease states. The present invention further relates to compositions comprising said 2,6,7-substituted pyrrolo[2,3-d]pyrimidines and methods for preventing, abating, or otherwise controlling enzymes which are understood to be the active components responsible for the herein described disease states.

1 . A compound, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is chosen from:
 i) substituted or unsubstituted C 6 -C 10  aryl; 
 ii) substituted or unsubstituted C 1 -C 6  linear or branched acyclic hydrocarbyl; 
 iii) substituted or unsubstituted C 1 -C 10  heterocyclic; and 
 iv) substituted or unsubstituted C 1 -C 10  heteroaryl; 
 R 1  is chosen from: 
 i) hydrogen; and 
 ii) substituted or unsubstituted C 6 -C 10  aryl; 
 R 2  is substituted or unsubstituted C 6 -C 10  aryl; 
 L and L 1  are linking units each of which is independently chosen from: 
 i) —NH—; 
 ii) —O—; 
 iii) —SO 2 —; 
 iv) —C(O)—; 
 v) —C═NOR 6 ; 
 vi) —C(R 6 ) 2 —; 
 vii) —C[═C(R 6 ) 2 ]—; and 
 viii) —C(OR 5 ) 2 —; 
 
       wherein R 5  is hydrogen, —COR 6 , or two R 5  units can be taken together with the oxygen atoms to form a cyclic ketal ring comprising 5 or 6 atoms; R is methyl, ethyl, or n-propyl. 
     
     
         2 . A compound according to  claim 1  wherein R is a substituted C 6 -C 10  aryl unit wherein said substitution is chosen from: halogen, C 1 -C 4  linear or branched alkyl, —OH, —OR 8 , —CN, —N(R 8 ) 2 , —CO 2 R 8 , —CON(R 8 ) 2 , —NR 8 COR 8 , and —NO 2 ; each R 8  is independently hydrogen, C 1 -C 4  alkyl, or two R 8  units can be taken together to form a ring comprising from 3-7 atoms. 
     
     
         3 . A compound according to  claim 2  wherein R is a C 6 -C 10  aryl unit chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, and 2,6-dichlorophenyl. 
     
     
         4 . A compound according to  claim 2  wherein R is a C 6 -C 10  aryl unit substituted with a unit chosen from:
 i) —CO 2 R 8 ;   ii) —CON(R 8 ) 2 ; and   iii) —NR 8 COR 8 ;   
       R 8  is hydrogen, methyl, or ethyl. 
     
     
         5 . A compound according to  claim 2  wherein R is a C 6 -C 10  aryl unit chosen from 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 2,6-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxy-phenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, and 2,6-dimethoxyphenyl. 
     
     
         6 . A compound according to  claim 1  wherein R is a substituted or unsubstituted 5-member ring C 1 -C 4  heterocyclic unit chosen from pyrrolidin-1-yl, pyrrolidin-4-yl, tetrahydrofuran-2-yl, imidazolidin-2-yl, and imidazolidin-4-yl. 
     
     
         7 . A compound according to  claim 1  wherein R is a substituted or unsubstituted 6-member ring C 1 -C 5  heterocyclic unit chosen from piperidin-1-yl, piperidin-4-yl, morpholin-4-yl, and pyran-4-yl. 
     
     
         8 . A compound according to  claim 1  wherein R is a substituted or unsubstituted C 1 -C 6  linear or branched alkyl unit having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 9 , R 10a , R 10b , and R 11  are each independently;
 i) hydrogen; 
 ii) C 1 -C 4  alkyl; 
 iii) —OH; or 
 iv) C 1 -C 4  alkoxy. 
 
     
     
         9 . A compound according to  claim 8  wherein R has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound according to  claim 1  wherein R 1  is a C 6 -C 10  aryl unit chosen from phenyl, 2-chlorphenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, and 2,6-dimethylphenyl. 
     
     
         11 . A compound according to  claim 1  wherein R 2  is a C 6 -C 10  aryl chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, and 2,6-dichlorophenyl. 
     
     
         12 . A compound according to  claim 1  wherein R 2  is a C 6 -C 10  aryl unit chosen from 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 2,6-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxy-phenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, and 2,6-dimethoxyphenyl. 
     
     
         13 . A compound according to  claim 1  wherein R 2  is a C 6 -C 10  aryl unit chosen from 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2,4-ditrifluoromethyl-phenyl, 3,5-ditrifluoromethylphenyl, 2,6-ditrifluoromethylphenyl, 2-aminophenyl, 3-amino-phenyl, 4-amino-phenyl, 2,4-diaminophenyl, 3,5-diaminophenyl, and 2,6-diaminophenyl. 
     
     
         14 . A compound according to  claim 1  wherein R 1  is a C 6 -C 10  aryl unit substituted with a unit chosen from:
 i) —CO 2 R 8 ;   ii) —CON(R 8 ) 2 ; and   iii) —NR 8 COR 8 ;   R 8  is hydrogen, methyl, or ethyl.   
     
     
         15 . A compound according to  claim 1  wherein L and L 1  are each independently chosen from:
 i) —NH—;   ii) —O—;   iii) —SO 2 —;   iv) —C(O)—; and   v) —CHOR 5 —.   
     
     
         16 . A compound, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is selected from the group consisting of:
 i) substituted or unsubstituted C 6 -C 10  aryl; 
 ii) substituted or unsubstituted C 1 -C 6  linear or branched acyclic hydrocarbyl; and 
 iii) substituted or unsubstituted C 1 -C 10  heterocyclic; 
 R 1  is selected from the group consisting of: 
 i) hydrogen; 
 ii) substituted or unsubstituted C 1 -C 6  linear, branched, or cyclic alkyl; and 
 iii) substituted or unsubstituted C 6 -C 10  aryl; 
 R is substituted or unsubstituted C 6 -C 10  aryl. 
 
     
     
         17 . A compound chosen from: 
       [7-(2,6-Difluorophenyl)-2-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone;
 (2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-(piperidin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; 
 (2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-(4-methyl-piperazin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; 
 (2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-(morpholin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; 
 
       [7-(2,6-Difluorophenyl)-2-(4-methyl-piperazin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone;
 (4-Fluorophenyl)-[7-(4-fluorophenyl)-2-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; 
 (2-Chlorophenyl)-[7-(4-fluorophenyl)-2-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; and 
 (2,4-Dimethylphenyl)-[7-(4-fluorophenyl)-2-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone. 
 
     
     
         18 . A compound chosen from:
 (2-Chlorophenyl)-[2-(2,6-difluorophenoxy)-7-(2,6-difluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone;   (2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone;   
       [7-(2,6-Difluorophenyl)-2-(2,6-difluorophenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone; 
       [7-(2,6-Difluorophenyl)-2-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone; 
       [2-(2,6-Difluorophenylamino)-7-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone;
 (4-Fluorophenyl)-[7-(4-fluorophenyl)-2-(1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; and 
 (2-Chlorophenyl)-[7-(4-fluorophenyl)-2-(1-phenyl-ethyl amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone. 
 
     
     
         19 . A compound chosen from: 
       N,N-Dimethyl-N′-[7-(2,6-difluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-2-hydrazino-(4-fluoro-phenyl)-methanone; 
       N,N-Dimethyl-N′-(2-chlorophenyl)-[7-(2,6-difluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-2-hydrazino-methanone; 
       (S)-(2-Chloro-phenyl)-[7-(2,6-difluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; 
       (S)-[2-sec-Butylamino-7-(2,6-difluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(2-chloro-phenyl)-methanone; 
       (S)-[7-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone;
 (2-Chloro-phenyl)-[7-(2,6-difluoro-phenyl)-2-methoxyamino-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; 
 
       (S)-(4-Fluoro-phenyl)-[7-(2-fluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; 
       [2-Cyclopropylamino-7-(2-fluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone;
 (2-Chloro-phenyl)-[7-(4-fluoro-phenyl)-2-(2-methoxy-1-methyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; 
 (S)-(4-Fluoro-phenyl)-[7-(4-fluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; 
 
       (S)-(2-Chloro-phenyl)-[7-(4-fluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; 
       (S)-[2-sec-Butylamino-7-(4-fluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(2-chloro-phenyl)-methanone;
 (2,4-Dimethyl-phenyl)-[7-(4-fluoro-phenyl)-2-(2-hydroxy-1,2-dimethylpropylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; 
 
       (S)-(2-Chloro-phenyl)-[7-(2,6-difluoro-phenyl)-2-(2-methoxy-1-methyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; and 
       (2-Chloro-phenyl)-[7-(2,6-difluoro-phenyl)-2-urylamino-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone. 
     
     
         20 . A compound chosen from: 
       [7-(2,6-Difluoro-phenyl)-2-(dimethylamin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone-oxime; 
       [7-(2,6-Difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone oxime;
 (2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone oxime; 
 (2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone oxime; 
 
       [7-(2,6-Difluorophenyl)-2-(dimethylamin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone O-methyl-oxime; 
       [7-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone O-methyl-oxime;
 (2-Chloro-phenyl)-[7-(2,6-difluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone O-methyl-oxime; 
 
       [7-(2,6-Difluoro-phenyl)-2-(piperidin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone O-methyl-oxime; 
       3{7-(2-Fluoro-phenyl)-6-[(4-fluoro-phenyl)-hydroxy-methyl]-7H-pyrrolo[pyrimidin-2-ylamino}-2-methyl-butan-2-ol; 
       Acetic acid (2-chloro-phenyl)-[7-(2,6-difluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]methylester; and 
       3-{7-(2,6-Difluoro-phenyl)-6-[2-(4-fluoro-phenyl)-[1,3]dioxolan-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino}-2-methyl-butan-2-ol 
     
     
         21 . A compound chosen from: 
       (2-Chlorophenyl)-[2-(N,N-dimethyl-N′-methylhydrazino)-7-(5-methyl-isoxazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; 
       (2-Chlorophenyl)-[2-(2-hydroxy-1,2-dimethyl-propylamino)-7-(5-methyl-isoxazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone; 
       2-(2-Chlorophenyl)-1-[7-(4-fluorophenyl)-2-(1-phenylethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone; 
       2-(2-Chlorophenyl)-1-[7-(4-fluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone; and 
       [6-Benzenesulfonyl-7-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-morpholin-4-yl-amine. 
     
     
         22 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is chosen from piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, pyran-4-yl, phenyl, 2,6-difluorophenyl, 2-methyl-2-hydroxy-1-(S)-methylpropyl, 2-methoxy-1-(S)-methylethyl, 2-methyl-2-cyano-1-(S)-methylpropyl, 1-(S)-methylpropyl, 2-methyl-2-hydroxy-1-(R)-methylpropyl, 2-methoxy-1-(R)-methylethyl, 2-methyl-2-cyano-1-(R)-methylpropyl, 1-(R)-methylpropyl, N,N-dimethylamino, and N,N-diethylamino;
 L is —NH— or —O—; 
 R 1  is chosen from: 
 i) hydrogen; and 
 ii) substituted or unsubstituted C 6 -C 10  aryl; and 
 R 2  is substituted or unsubstituted C 6 -C 10  aryl. 
 
     
     
         23 . A composition comprising:
 a) an effective amount of one or more 2,6,7-substituted pyrrolo[2,3-d]pyrimidines and derivatives thereof according to  claim 1 ; and   b) one or more pharmaceutically acceptable excipients.   
     
     
         24 . A method for treating rheumatoid arthritis or osteoarthritis comprising the step of administering to a human or higher mammal an effective amount of a composition comprising one or more compounds according to  claim 1 . 
     
     
         25 . A method for treating disease states which relate to connective tissue degradation comprising the step of administering to a human or higher mammal an effective amount of a composition comprising one or more compounds according to  claim 1 . 
     
     
         26 . A method for inhibiting cycloxygenase-2 comprising the step of administering to a human or higher mammal an effective amount of a composition comprising one or more compounds according to  claim 1 . 
     
     
         27 . A method for treating inflammatory bowel disease, septic shock, cardiopulmonary dysfunction, acute respiratory disease, and cachexia comprising the step of administering to a human or higher mammal an effective amount of a composition comprising one or more compounds according to  claim 1 .